Virtually all of the many antineoplastic drugs that are currently used in the treatment of cancer have very serious and harmful side effects. This is because cancer is generally treated with medications that interfere with the growth of rapidly dividing cells. Such medications can inhibit the growth of the cancer cells, but they almost always also inhibit the growth of normal cells that divide rapidly in the body. Some of the normal tissues that divide very rapidly include bone marrow (which produces blood cells), hair follicles, and intestinal epithelium. The usefulness of virtually all antineoplastic drugs is severely limited by the damage they cause to these normal tissues.
This invention relates to methods for treating neoplasia using both an antineoplastic platinum coordination complex (a common chemotherapeutic) and a cyclic GMP (cGMP)-specific phosphodiesterase (PDE) inhibitor to reduce the side effects or increase the efficacy of treatment with an antineoplastic platinum coordination complex. Under current practices, platinum complexes (e.g., cisplatin and carboplatin) are typically used to treat certain cancers, particularly ovarian and testicular cancers.
Cisplatin (cis-diaminedichloroplatinum) is a heavy metal complex with a central platinum atom surrounded by two ammonia molecules and two chlorine atoms in the cis position. Cisplatin is also known by the trade name Platinol.
Cisplatin is typically used as a secondary therapy in combination with other chemotherapeutic agents for metastatic testicular tumors and metastatic ovarian tumors in patients who have already received appropriate surgical or radiotherapeutic treatment. Cisplatin is also used as a single agent in treating patients with transitional cell bladder cancer which is not suited for surgical or radiotherapeutic treatment. Cisplatin has been used in treating epithelial malignancies as well as cancers of the head and neck, the esophagus, and the lung.
Cisplatin appears to enter cells by diffusion. The chlorine atoms of cisplatin are subject to chemical displacement by nucleophiles, such as water or sulfhydryl groups. The activated species of the drug reacts with nucleic acids and proteins. Platinum complexes can react with DNA, forming both intrastrand and interstrand crosslinks, which inhibit DNA replication and RNA transcription and can lead to breaks and miscoding. The platinum from cisplatin also becomes bound to several plasma proteins including albumin, transferrin, and gamma globulin which may interfere with a number of cellular functions.
The major dose-limiting toxicity of cisplatin is cumulative renal insufficiency which has been associated with renal tubular damage. Renal toxicity becomes more prolonged and more severe with repeated cisplatin treatments. Electrolyte disturbances are often secondary effects of renal damage. Hydration and diuresis are used to reduce renal toxicity, but renal damage often occurs even if these measures are taken.
Myelosuppression is another dose-related toxicity of cisplatin treatment, characterized by a decrease in the levels of leukocytes and platelets. Leukocytes are white blood cells which fight off infection, and platelets are necessary for proper blood clotting. Anemia is another side effect of treatment with cisplatin.
Toxic reactions in the ears, or otoxicity is another effect of cisplatin treatment. This can be manifested by tinnitus, or noises such as ringing or whistling in the ears, loss of high frequency hearing, and occasionally deafness. It is unclear whether cisplatin-related ototoxicity is reversible.
Other side effects of cisplatin include gastrointestinal effects such as nausea and vomiting which occur in almost all patients treated with cisplatin. Anaphylactic-like reactions may occur shortly after administration of the drug.
Cisplatin is a member of the family of platinum coordination complexes. There are numerous derivatives of cisplatinum including carboplatin and oxaliplatin. Carboplatin (Paraplatin), like cisplatin, is thought to produce interstrand DNA cross-links. It is currently used in the treatment of patients with ovarian cancer that has recurred after chemotherapy. Clinically, there is less nephrotoxicity with carboplatin than with cisplatin, and the dose-limiting toxicity with carboplatin is myelosupression, primarily as thrombocytopenia, or a decrease in the of platelets circulating in the blood.
This invention relates to an improved method of cancer therapy that involves treating a patient with both an antineoplastic platinum coordination complex (i.e., a cisplatin derivative, which includes both cisplatin and derivatives thereof such as carboplatin) and a cGMP-specific phosphodiesterase (PDE) inhibitor. The specific PDE inhibitors useful for this invention are compounds that inhibit both PDE5 and the new cGMP-specific PDE described below. The novel cGMP-PDE is fully described by, Liu, et al., in the copending U.S. patent application Ser. No. 09/173,375, now U.S. Pat. No. 6,200,771, A Novel Cyclic GMP-Specific Phosphodiesterase And Methods For Using Same In Pharmaceutical Screening For Identifying Compounds For Inhibition Of Neoplastic Lesions. (For general PDE background, see, Beavo, J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiological Reviews 75:725-747; web site  less than http://weber.u.washington.edu/xcx9cpde/pde.html greater than  (November 1998)).
In this invention, the cGMP-specific PDE inhibitor can be used in combination with an antineoplastic platinum coordination complex in two ways. The first is a lower dosage methodology in which the traditionally recommended dose range of the cisplatin derivative is decreased while its therapeutic effects are maintained and its side effects are attenuated. The second is a higher dosage methodology that utilizes the traditionally recommended dose range for the cisplatin derivative and improves its activity without increasing its side effects. With each methodology, the cisplatin derivative is administered simultaneously with or in succession with an appropriate cGMP-specific PDE inhibitor.
In the low dose regime, a cisplatin derivative is administered at doses less than about 75 mg/m2. In the high dose regime, a cisplatin derivative is administered at doses between about 75 and 100 mg/m2.